Compressed-molded preparations

ABSTRACT

Compressed molded preparations are disclosed. In the preparation coated granules of a pharmaceutical composition are compressed and molded together with non-coated component(s) containing 10% or more by weight of non-swelling polymers. According to the preparation there is little breakdown of the coating of coated granules at the time of compressing and molding, and the rate of disintegration, and in turn, the release rate of the pharmaceutical component, can be freely controlled or modulated.

This is a division of application Ser. No. 07/293,108, filed on Jan. 03,1989 U.S. Pat. No. 5,186,943.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to compressed-molded preparations in whicha composition comprising coated granules of a pharmaceutical componentis compressed and molded to give a single dosage form. Moreparticularly, the invention relates to compressed-molded preparations inwhich there is little breakdown of the coating of coated granules at thetime of compressing and molding, and also, to preparations in which therate of disintegration, and in turn, the release rate of thepharmaceutical component, can be freely controlled or modulated.

2. Description of the Background

It is well known that granules coated with coatings possessing waterinsoluble, intestinally soluble, acid soluble, or water soluble featurescan be used in order to obtain granules having sustained-releasecharacteristics, or taste- and smell-masking characteristics. However,when the coated granules are processed to form compressed-molded tabletpreparations, the coating of the coated granule is very often destroyedby the pressure which is applied, thus damaging the function of thecoatings. Since advanced and sophisticated technologies are neededbecause of this reason, coated granule preparations are usually marketedas they are or in capsule form.

As a means to solve such problems, a method for preparing tablets whichinvolves using microcrystalline cellulose together with the coatedgranules has been proposed (Japanese Patent Laid-open No. 221115/1986).However, when a large amount of microcrystalline cellulose is used inthe non-coated component, the stability of the active components may belost or damaged, or the manufacturing procedure of the preparation maybecome difficult, depending upon the form of the non-coated component,or the active drug ingredient or the compound used for producing thecoated granules. Also, because the disintegrability of microcrystallinecellulose is high, it is difficult to control the rate of movement ofthe coated granules in the alimentary canal, as well as the release rateof the active ingredient from the non-coated component.

In view of such a present situation, the inventors carried out researchrelated to compressed-molding of compositions containing coatedgranules. As a result of the research, it was discovered that byformulating a non-swelling polymer into the non-coated components,compressed-molded preparations could be obtained which were hard enoughfor practical use, and yet of which coating applied to the coatedgranules was resistant to destruction. Also, it was found that thedisintegration characteristics of the compressed-molded preparations aswell as the release charactertics of the active ingredient could befreely controlled or modulated by controlling the amount of non-swellingpolymers to be formulated and also by adding disintegrators, waxes, etc.Such findings have led to the completion of the present invention.

SUMMARY OF THE INVENTION

Accordingly, an object of this invention is to provide compressed-moldedpreparations, in which coated granules of a pharmaceutical compositionare compressed and molded together with non-coated component(s)containing 10% or more by weight of non-swelling polymers.

Another object of this invention is to provide said compressed-moldedpreparations, wherein said coated granules are comprised of thepharmaceutical composition which is coated with a layer of one or moremembers selected from the group consisting of water insoluble polymers,intestinally soluble polymers, paraffin waxes, higher alcohols, higherfatty acid esters, and higher fatty acids or their salts.

Still another object of this invention is to provide saidcompressed-molded preparations possessing, on top of said layer of acoated material, a protective coating layer of a water soluble polymeror an acid soluble polymer.

One more object of this invention is to provide compressed-moldedpreparations, wherein said coated granules are comprised of apharmaceutical composition (comprising diclofenac sodium and an organicacid) on which a sustained-release coating is coated.

Other objects, features and advantages of the invention will hereinafterbecome more readily apparent from the following description.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

In the present invention, the coated granule can be any pharmaceuticalcomposition which is produced by conventional granulation methods,inasmuch as the same contains an active ingredient and possesses acoating.

There is no particular limitation or restriction as to the compound usedas the coating. Specific examples which can be given include waterinsoluble polymers such as ethylcellulose, aminoalkyl methacrylatecopolymer, polyvinyl acetate, polyvinyl chloride, polyethylene, and thelike; intestinally soluble polymers such as cellulose acetate phthalate,hydroxypropyl methyl cellulose phthalate, hydroxypropyl methylcelluloseacetate succinate, carboxymethylethylcellulose, styrene-acrylic acidcopolymer, methacrylic acid copolymer, maleic anhydride copolymer,shellac, and the like; paraffin waxes such as paraffin, microcrystallinewax, and the like; higher alcohols such as stearyl alcohol, cetylalcohol, and the like; higher fatty acid esters such as glycerine estersof fatty acid, hydrogenated oils, carnauba wax, beeswax, Japan (haze)wax, and the like; higher fatty acids such as stearic acid, palmiticacid, myristic acid, behenic acid, and the like (or the sodium, calciumor magnesium salts of these higher fatty acids), acid soluble polymerssuch as polyvinylacetal diethylaminoacetate, aminoalkyl methacrylatecopolymer E, and the like; and water soluble polymers such ashydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose,polyvinyl pyrrolidone, polyethylene glycol, gelatin, and the like. Thesecompounds can be used alone or in combinations of two or more.

Also, coated granules with a primary coating layer comprising one ormore types of compounds amoung from water insoluble polymers,intestinally soluble polymers, paraffin waxes, higher alcohols, fattyacid esters, and higher fatty acid or their salts, on the pharmaceuticalcomposition, and further with a protective coating on top of thisprimary coating layer which is comprised of water soluble or acidsoluble polymers, can provide even greater protection againstdestruction of the coating at the time of compressing-molding.

Here, the same compounds as mentioned previously are used as the coatingfor the primary coating and the protective coating.

A pharmaceutical composition which comprises diclofenac sodium as anactive ingredient together with an organic acid, if applied asustained-release coating to form coated granules, can be made into along-lasting preparation which gives a decreased maximum plasmadiclofenac concentration, causes decreased side effects, and yetmaintains a constant plasma diclofenac concentration for a prolongedtime.

There is no particular limitation or restriction on the organic acidswhich can be used. Specific examples which can be given include citricacid, ascorbic acid, fumaric acid, tartaric acid, succinic acid, malicacid, and adipic acid, as well as mixtures of any of these compounds. Itis desirable to formulate 2 parts or more by weight of organic acid to100 parts by weight of diclofenac sodium.

As the sustained-release coating, the previously mentioned waterinsoluble polymers, intestinally soluble polymers, paraffin waxes,higher alcohols, higher fatty acid esters, higher fatty acids or theirsalts, and the like, can be given as examples. These compounds can beused alone or in combinations of two or more.

The coated granules are produced by various methods. One method involvesgranulating the pharmaceutical composition by a conventional method andthen applying a coating to the granules. Another involves producingcoated granules by methods such as microencapsulation of thepharmaceutical composition.

The amounts of coating materials differ depending upon the type of thecoated materials. Normally, it accounts for 1 to 80%, on a weight basis,of the pharmaceutical composition, with 3 to 60% being the mostdesirable.

The compressed-molded preparations of the present invention can beprepared using non-coated components containing the non-swellingpolymers as is, or after processing such components into powder fortablet use by using dry or wet granulation methods. Such non-coatedcomponents or the powders are then mixed with the granules of coatingmaterial and molded by any of known compression-molding methods.

The desirable non-swelling polymers for use here are those possessing ahigh degree of compressability/moldability, as well as a low degree ofdisintegration characteristic. Specific examples which can be giveninclude water insoluble polymers such as ethylcellulose, aminoalkylmethacrylate copolymer, polyvinyl acetate, polyvinyl chloride,polyethylene, and the like; intestinally soluble polymers such ascellulose acetate phthalate, hydroxypropyl methylcellulose phthalate,hydroxypropyl methylcellulose acetate succinate,carboxymethylethylcellulose, styreneacrylic copolymer, methacrylic acidcopolymer, maleic anhydride copolymer, and the like; acid solublepolymers such as polyinylacetal diethylamino acetate, aminoalkylmethacrylate copolymer E, and the like; and water soluble polymers suchas hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, and the like. These compounds can beused alone or in combinations of two or more.

In order to prevent the destruction of the coating of the coatedgranules and to control or modulate the disintegration characteristicsof the coating, the amount of the non-swelling polymers to be formulatedmust be greater than 10% by weight of the amount of the non-coatedcomponents. It is possible to formulate the active ingredient into thesenon-coated components. In particular, when the drug ingredient isdiclofenac sodium, a preparation having an excellent prolonged effectcan be obtained, if the percentage of non-coated diclofenac sodium addedto the non-coated components is between 10 and 50%, especially 20 to40%, on a weight basis, of the total amount of diclofenac sodium.

To the compressed-molded preparation of the present invention,appropriate, well known substances, such as vehicles, binders,disintegrators, disintegration retarding agents, lubricants, coloringagents, flavoring substances, stabilizers, and the like can beformulated as desired.

The compressed-molded preparation obtained in this way can also beprocessed into a film-coated tablet, a sugar-coated tablet, apress-coated tablet, or a multi-layered tablet.

The compressed-molded preparation thus prepared according to the presentinvention, when combined with the special characteristics of the coatinggranule, or also, with the special characteristics of the activeingredient, can be used as a single dosage form which is hard enough forpractical use, without impairing the function of the coating of thecoated granule. In addition, the release rate of the active componentfrom the non-coated component, as well as the disintegration time of thecompressed-molded preparation, can be controlled or modulated.

Therefore, the preparations are easier to administer and can impart amore prolonged drug effect than sustained-release preparations usingcoated granules alone.

Other features of the invention will become apparent in the course ofthe following description of the exemplary embodiments which are givenfor illustration of the invention and are not intended to be limitingthereof.

EXAMPLES Example 1

1) Preparation of Non-coated Granules (a):

800 g of diclofenac sodium was mixed with 280 g of corn starch andpulverized, resulting in fine powders. These fine powders were processedto produce spherical granules, using 720 g of purified sucrose that hadbeen obtained by shifting through 20-28 mesh as a core, while pouring asolution of hydroxypropyl cellulose (25 g) which had been dissolved in475 g of ethyl alcohol. The granules were then dried for 3 hours at 55°C. These dried granules were then passed through a 14 mesh followed bypassage through a 28 mesh. The granules which did not go through the 28mesh were taken as non-coated granules (a).

2) Preparation of Coated Granules (b):

Coated granules (b) were produced according to a conventional spraycoating method as follows: 600 g of non-coated granules (a) producedin 1) above was placed into a fluid-type coating apparatus, followed bysparay coating using 1263 g of the coating liquid having the compositionlisted below. The weight of the coating with respect to the weight ofthe non-coated granule was 8%.

    ______________________________________                                        Composition of Coating Liquid                                                                      %                                                        ______________________________________                                        Ethylcellulose       2.7                                                      Polyvinylpyrrolidone K-30                                                                          0.9                                                      Talc                 0.2                                                      Ethyl alcohol        96.2                                                     Total                100.0                                                    ______________________________________                                    

Example 2

Preparation of Coated Granule (c):

Coated granules (c) were produced according to a conventional spraycoating method as follows: 600 g of non-coated granule (a) obtained inExample 1 was placed into a fluid-type coating apparatus, followed byspray coating using 1667 g of the coating liquid having the compositionlisted below. The weight of the coating with respect to the weight ofthe non-coated granules was 20%.

    ______________________________________                                        Composition of Coating Liquid                                                                      %                                                        ______________________________________                                        Aminoalkyl methacrylate                                                                            6.5                                                      copolymer L                                                                   Glycerin ester of fatty acid                                                                       0.5                                                      Talc                 0.2                                                      Ethyl alcohol        92.8                                                     Total                100.0                                                    ______________________________________                                    

Example 3

i) Preparation of Compressed-Molded Preparation (d-1):

500 g of the non-coated granules (a) produced in 1), Example 1, wasplaced in a small coating pan. The pan was rotated at 35 rpm whilesending hot air through at 90° C. 40 g of hydrogenated castor oil waspoured and when the hydrogenated oil began to melt, 80 g of magnesiumstearate was added in five 16 g portions to make it adhered onto thegranules. In the same way, 40 g of hydrogenated castor oil was pouredand 80 g of magnesium magnesium stearate were added in five 16 gportions to make it adhered onto the granules. The same operation wasrepeated again to produce coated granules (d-1). The weight of thecoating with respect to the weight of the non-coated granule was 72%.

ii) Preparation of Compressed-molded Preparation (d-2)

294.3 g of the coated granules produced in 1) above, 263.7 g ofethylcellulose, 30 g of carboxymethylcellulose calcium, 6 g of lightanhydrous silicic acid, 3 g of magnesium stearate, and 3 g of talc wereuniformly mixed, and then compressed and molded to produce compressedmolded tablets (d-2) of the present invention, each tablet having aweight of 300 mg and a diameter of 9 mm.

Example 4

Preparation of Compressed-Molded Preparation (e):

246.3 g of coated granules (b) produced in 2) of Example 1, 300 g ofethylcellulose, 11.7 g of lactose, 30 g of carboxymethylcellulosecalcium, 6 g of light anhydrous silicic acid, 3 g of magnesium stearate,and 3 g of talc were uniformly mixed and then compressed and molded. Thecompress-molded tablet (e) of the present invention thus obtained eachweighed 300 mg and had a diameter of 9 mm.

Test Example 1

The dissolution of active ingredient from compressed-molded preparation(e) obtained in Example 4 and coated granules (b) obtained in 2) ofExample 1 were measured by the rotating paddle method (JapanPharmacopeia--11th Edition) using a pH 6.8 buffer as a test solution.The results are shown in Table 1. It was found that there were almost nochanges in the dissolution of active ingredient from coating granule (b)(prior to compression and molding) and the present inventioncompressed-molded preparation (e) (after compression-molding).

                  TABLE 1                                                         ______________________________________                                        Time        Dissolution (%)                                                   (hr)        Example 4 2) of Example 1                                         ______________________________________                                        1           40.2      38.7                                                    3           82.9      79.2                                                    ______________________________________                                    

Example 5

i) Preparation of Compressed-Molded Preparation (f-1):

70 g of an aqueous solution of hydroxypropyl cellulose (10% w/w) wasadded to a powder mixture consisting of 300 g of ethylcellulose, 118 gof lactose, and 25 g of corn starch. The mixture was then kneaded andgranules were produced according to a conventional method. Next, 253.55g of the resulting granules, 68.45 g of coated granules (c) from Example2, 20 g of carboxymethylcellulose calcium, 4 g of light anhydroussilicic acid, 2 g of magnesium stearate, and 2 g of talc were uniformelyblended, and compressed and molded. The resulting tablets,compressed-molded preparation (f-1) of the present invention, eachweighed 350 mg and had a diameter of 9 mm.

ii) Preparation of Compressed-Molded Preparation (f-2):

70 g of an aqueous solution of hydroxypropyl cellulose (10% w/w) wasadded to a powder mixture consisting of 200 g of ethylcellulose, 218 gof lactose, and 25 g of corn starch. The mixture was then kneaded andgranules were produced according to a conventional method. Next, 253.55g of the resulting granules were uniformly mixed with 68.45 g of coatedgranules (c) from Example 2, 20 g of carboxymethylcellulose calcium, 4 gof light anhydrous salicic acid, 2 g of magnesium stearate, and 2 g oftalc. The mixture was then compressed and molded. The resulting tablets,compressed-molded preparation (f-2) of the present invention, eachweighed 350 mg and had a diameter of 9 mm.

iii) Preparation of Compressed-Molded Preparation (f-3):

70 g of an aqueous solution of hydroxypropyl cellulose (10% w/w) wasadded to a powder mixture consisting of 100 g of ethylcellulose, 318 gof lactose, and 25 g of corn starch. The mixture was then kneaded andgranules were produced according to a conventional method. Next, 253.55g of the granules obtained was uniformly mixed with 68.45 g of coatedgranules (c) from Example 2, 20 g of carboxymethylcellulose calcium, 4 gof light anhydrous silicic acid, 2 g of magnesium stearate, and 2 g oftalc. The mixture was then compressed and molded to obtain tablets, thecompressed-molded preparation (f-3) of the present invention, eachweighing 350 mg and having a diameter of 9 mm.

Comparative Example 1

Preparation of Regular Compressed-Molded Preparation (g):

70 g of an aqueous solution of hydroxypropyl cellulose (10% w/w) wasadded to a powder mixture consisting of 200 g of mannitol, 218 g oflactose, and 25 g of corn starch. The mixture was then kneaded andgranules were produced according to a conventional method. Next, 253.55g of the granules obtained was mixed together with 68.45 g of coatedgranules (c) from Example 2, 20 g of carboxymethylcellulose calcium, 4 gof light anhydrous silicic acid, 2 g of magnesium stearate, and 2 g oftalc. The mixture was then uniformly blended and compressed and molded.The resulting tablets each weighed 350 mg and had a diameter of 9 mm.These tablets were taken as regular compressed-molded preparation (g).

Test Example 2

The dissolution of active ingredient from compressed-molded preparations(f-1), (f-2), and (f-3) from Example 5 and compressed-molded preparation(g) obtained from Comparative Example 1 were measured by the rotatingpaddle method (Japan Pharmacopeia, 11th Edition) using a pH 4.5 bufferas a test solution. The results are shown in Table 2. Compared tocompressed-molded preparation (g), the effectiveness of thecompressed-molded preparations in ethylcellulose of the presentinvention was clear. Also, as the percentage of ethylcellulose in thenon-coated component was increased, destruction of the coating of thecoated granule could be prevented.

                  TABLE 2                                                         ______________________________________                                        Dissolution (%)                                                               Time                         Regular compressed-                              (min)   (f-1)  (f-2)    (f-3)                                                                              molded preparation (g)                           ______________________________________                                        30      2.8    4.7      8.5  52.6                                             ______________________________________                                    

Example 6

i) Preparation of Compressed-Molded Preparation (h-1):

80 g of an aqueous solution of hydroxypropyl cellulose (10% w/w) wereadded to a powder mixture consisting of 23.3 g of diclofenac sodium, 240g of ethyl cellulose, 153.7 g of lactose, and 25 g of corn starch. Themixture was then kneaded and granules were produced according to aconventional method. Next, 241.55 g of the granules obtained were mixedwith 68.45 g of coated granules (c) from Example 2, 32 g ofethylcellulose, 4 g of light anhydrous silicic acid, 2 g of magnesiumstearate, and 2 g of talc. The mixture was uniformly blended and thencompressed and molded. Each of the resulting tablets weighed 350 mg andhad a diameter of 9 mm. These tablets were taken as compressed-moldedpreparation (h-1) of the present invention.

ii) Preparation of Compressed-Molded Preparation (h-2):

80 g of an aqueous solution of hydroxypropyl cellulose (10% w/w) wasadded to a powder mixture consisting of 23.3 g of diclofenac sodium, 240g of ethylcellulose, 153.7 g of lactose, and 25 g of corn starch. Themixture was then kneaded and granules were produced according to aconventional method. Next, 241.55 g of the granules obtained was mixedwith 68.45 g of coated granules (c) from Example 2, 22 g ofethylcellulose, 10 g of carboxymethyl-cellulose, 4 g of light anhydroussilicic acid, 2 g of magnesium stearate, and 2 g of talc. The mixturewas uniformly blended and then compressed and molded. Each of theresulting tablets weighed 350 mg and had a diameter of 9 mm. Thesetablets were taken as compressed-molded preparation (h-2) of the presentinvention.

iii) Preparation of Compressed-Molded Preparation (h-3):

80 g of an aqueous solution of hydroxypropyl cellulose (10% w/w) wasadded to a powder mixture consisting of 23.3 g of diclofenac sodium, 240g of ethylcellulose, 153.7 g of lactose, and 25 g of corn starch. Themixture was then kneaded and granules were produced according to aconventional method. Next, 241.55 g of the granules, obtained was mixedwith 68.45 g of coated granules (c) from Example 2, 8 g of ethylcellulose, 24 g of carboxymethyl-cellulose calcium, 4 g of lightanhydrous silicic acid, 2 g of magnesium stearate, and 2 g of talc. Themixture was uniformly blended and then compressed and molded. Each ofthe resulting tablets weighed 350 mg and had a diameter of 9 mm. Thesetablets were taken as compressed-molded preparation (h-3) of the presentinvention.

Comparative Example 2

Preparation of Regular Compressed-Molded Preparation (i):

80 g of an ethyl alcohol solution of hydroxypropyl cellulose (10% w/w)was added to a powder mixture consisting of 20.6 g of diclofenac sodium,240 g of microcrystalline cellulose, 156.4 g of lactose and 25 g of cornstarch. The mixture was then kneaded and granules were producedaccording to a conventional method. Next, 273.55 g of the granulesobtained was mixed with 68.45 g of coated granules (c) from Example 2, 4g of light anhydrous silicic acid, 2 g of magnesium stearate, and 2 g oftalc. The mixture was uniformly blended and then molded and compressed.Each of the resulting tablets weighed 350 mg and had a diameter of 9 mm.These tablets were taken as regular compressed-molded preparations (i).

Test Example 3

The dissolution of active ingredient from compressed-molded preparations(h-1), (h-2) and (h-3) obtained from Example 6 and compressed-moldedpreparation (i) obtained from Comparative Example 2 were measured by therotating paddle method (Japan Pharmacopeia, 11th Edition) using a pH 4.5buffer as a test solution. The results are shown in Table 3. It wasfound that the elution rate of the rapid dissolving portion of thecompressed-molded preparation of the present invention could becontrolled or modulated, however, for regular compressed-moldedpreparation (i), it was difficult to control or modulate the dissolutionof active ingredient from the rapid dissolving portion.

                  TABLE 3                                                         ______________________________________                                        Dissolution (%)                                                               Time                         Regular compressed-                              (min)   (h-1)  (h-2)    (h-3)                                                                              molded preparation (i)                           ______________________________________                                        30       9.1   25.6     37.5 34.5                                             60      18.6   37.8     38.1 35.2                                             ______________________________________                                    

Test Example 4

The disintegration test (Japan Pharmacopeia, 11th Edition) using wateras the test fluid was carried out on compressed-molded preparations(h-1), (h-2) and (h-3) obtained from Example 6 and compressed-moldedpreparation (i) obtained from Comparative Test 2. The results are shownin Table 4. It was found that the disintegration times of thecompressed-molded preparations of the present invention were controlled.

                  TABLE 4                                                         ______________________________________                                        Disintegration Time (min)                                                                              Regular compressed-                                  (h-1)  (h-2)      (h-3)  molded preparation (i)                               ______________________________________                                        92     32         3      2                                                    ______________________________________                                    

Example 7

800 g of theophylline and 400 g of corn starch were mixed andpulverized, resulting in fine powders. These fine powders were processedto produce spherical granules, using 600 g of purified sucrose that hadbeen obtained by shifting through 28-35 mesh as a core, while pouring asolution of hydroxypropyl cellulose (25 g) which had been dissolved in475 g of ethyl alcohol. The granules were then dried for 3 hours at 55°C. Non-coated granules (j) were taken as those dried granules whichwould pass through a 16 mesh but not a 32 mesh. Coated granules (k) wereproduced by a conventional spray coating method as follows: 600 g ofnon-coated granules (j) was placed into a fluid-type coating apparatus,followed by spray-coating using 1263 g of the coating fluid having acomposition presented below. The weight of this coating with respect tothe weight of the non-coated granules was 8%.

    ______________________________________                                        Composition of Coating Liquid                                                                      %                                                        ______________________________________                                        Ethylcellulose       2.4                                                      Polyvinylpyrrolidone K-30                                                                          1.2                                                      Talc                 0.2                                                      Ethyl alcohol        96.2                                                     Total                100.0                                                    ______________________________________                                    

246.3 g of coated granules (k), 300 g of ethylcellulose, 41.7 g oflactose, 6 g of light anhydrous silicic acid, 3 g of magnesium stearate,and 3 g of talc were uniformly mixed, followed by compressing andmolding. Each tablet weighed 300 mg and had a diameter of 9 mm. Thesetablets were taken as compressed-molded preparation (1).

Example 8

800 g of indomethacin and 400 g of corn starch were mixed andpulverized, resulting in fine powders. These fine powders were processedto produce spherical granules, using 600 g of purified sucrose that hadbeen obtained by shifting through 28-35 mesh as a core, while pouring aliquid consisting of 25 g of hydroxypropyl cellulose dissolved in 475 gof ethyl alcohol. The granules were dried for 3 hours at 55° C.Non-coated granules (m) were taken as those granules which would passthrough a 16 mesh but not a 32 mesh. Coated granules (n) were producedby a conventional spray coating method as follows: 600 g of non-coatedgranules (m) was placed into a fluid-type coating apparatus, followed byspray-coating using 1263 g of the coating liquid having a compositionpresented below. The weight of this coating with respect to the weightof the non-coated granules was 8%.

    ______________________________________                                        Composition of Coating Liquid                                                                      %                                                        ______________________________________                                        Ethylcellulose       3.0                                                      Polyvinylpyrrolidone K-30                                                                          0.6                                                      Talc                 0.2                                                      Ethyl alcohol        96.2                                                     Total                100.0                                                    ______________________________________                                    

246.3 g of coated granule (n), 50 g of indomethacin, 250 g of ethylcellulose, 41.7 g of lactose, 6 g of light anhydrous silicic acid, 3 gof magnesium stearate, and 3 g of talc were uniformly mixed and thencompressed and molded. Each of the resulting tablets weighed 300 mg andhad a diameter of 9 mm. These tablets were taken as compressed-moldedpreparation (o) of the present invention.

Example 9

1) Preparation of Non-coated Granule (p):

525 g of diclofenac sodium and 285 g of corn starch were mixed andpulverized, resulting in fine powders. These fine powders were processedto produce spherical granules, using 420 g of purified sucrose that hadbeen obtained by shifting through 24-28 mesh as a core, while pouring aliquid consisting of 25.2 g of hydroxypropyl cellulose dissolved in478.8 g of ethyl alcohol. The granules were dried for 3 hours at 55° C.Non-coated granules (p) were taken as those dried granules which passedthrough 14 mesh but not 32 mesh.

2) Preparation of Primary Coated Granule (q):

Primary coated granules (q) were produced by placing 1000 g ofnon-coated granule (p) into a fluid-type coating apparatus, followed byspray coating using 3472 g of the coating fluid having a compositionshown below according to a conventional method. The weight of thiscoating with respect to the weight of the non-coated granule was 25%.

    ______________________________________                                        Composition of Coating Liquid                                                                      %                                                        ______________________________________                                        Dimethyl methacrylate                                                                              6.5                                                      copolymer-S                                                                   Glycerin ester of fatty acid                                                                       0.5                                                      Talc                 0.2                                                      Ethyl alcohol        92.8                                                     Total                100.0                                                    ______________________________________                                    

3) Preparation of Granule (r) Possessing a Protective Coating:

Granule (r) possessing a protective coating was produced according to aconventional spray coating method as follows: 600 g of primary coatedgranule (q) was placed into a fluid-type coating apparatus, followed byspray-coating using 1667 g of the coating liquid having a compositionshown below. The weight of this coating with respect to the weight ofthe primary coating (q) was 20%.

    ______________________________________                                        Composition of Coating Liquid                                                                       %                                                       ______________________________________                                        Hydroxypropyl methylcellulose                                                                       6.5                                                     Macrogol 6000         0.5                                                     Talc                  0.2                                                     Ethyl alcohol         66.8                                                    Purified water        26.0                                                    Total                 100.0                                                   ______________________________________                                    

4) Preparation of Compressed-Molded Preparation (s):

512 g of an aqueous solution of hydroxypropyl cellulose (10% w/w) wasadded to a powder mixture consisting of 45 g of diclofenac sodium, 694.8g of ethylcellulose, 90 g of lactose, 42.4 g of corn starch, 79.6 g ofcroscarmellose sodium type-A, and 118.8 g of low-substitutedhydroxypropyl cellulose. The mixture was then kneaded and granules wereproduced according to a conventional method. Next, 560.9 g of thegranules obtained was mixed with 188.28 g of granule (r) possessing theprotective coating, 34.82 g of microcrystalline cellulose, 8 g of lightanhydrous silicic acid, 4 g of magnesium stearate, and 4 g of talc. Themixture was uniformly blended and compressed and molded. The resultingtablets each weighed 200 mg and had a diameter of 8 mm. These tabletswere taken as compressed-molded preparation (s) of the presentinvention.

Test Example 5

The dissolution of active ingredient from compressed-molded preparation(s) of the present invention obtained in Example 9 and that of the finepowders for tablet used prior to compression-molding were measured bythe rotating paddle method (Japan Pharmacopeia, 11th Edition) using a pH4.5 buffer as a test solution. The results are shown in Table 5. It wasfound that there were no changes in the dissolution of active ingredientfrom the compressed-molded preparation of the present invention beforeor after compression-molding.

                  TABLE 5                                                         ______________________________________                                                   Dissolution (%)                                                    Time                fine powders for tablet                                   (min)        (s)    use for (s)                                               ______________________________________                                        30           33.1   32.1                                                      ______________________________________                                    

Example 10

1) Preparation of Non-coated Granules (t):

525 g of diclofenac sodium, 130 g of fumaric acid, 55 g of talc, and 10g of corn starch were mixed and pulverized to form fine powders. Thesefine powders were processed to produce spherical granules, using 480 gof purified sucrose that had been obtained by shifting through 24-28mesh as a core, while pouring a liquid consisting of 27 g ofhydroxypropyl cellulose dissolved in 513 g of ethyl alcohol. Thegranules were dried for 3 hours at 55° C. Non-coated granules (t) weretaken as the dried granules which passed through 14 mesh but not 32mesh.

2) Preparation of Coated Granules (u):

Coated granules (u) were produced according to a conventional spraycoating method as follows: 600 g of non-coated granules (t) was placedinto a fluid-type coating apparatus followed by spray-coating using 2083g of the coating liquid having a composition shown below. The weight ofthis coating with respect to the weight of the non-coated granule was25%.

    ______________________________________                                        Composition of Coating Liquid                                                                        %                                                      ______________________________________                                        Aminoalkyl methacrylate opolymer S                                                                   6.5                                                    Glycerin ester of fatty acid                                                                         0.5                                                    Talc                   0.2                                                    Ethyl alcohol          92.8                                                   Total                  100.0                                                  ______________________________________                                    

3) Preparation of Compressed-Molded Preparation (v):

240 g of an aqueous solution of 10% hydroxypropyl methylcellulose wereadded to a powder mixture consisting of 45 g of diclofenac sodium, 500 gof ethylcellulose, 119 g of lactose, 40 g of corn starch, and 24 g ofcroscarmellose sodium Type A. The mixture was then kneaded and granuleswere produced by a conventional method. Next, 188 g of the granulesobtained were mixed with 76.7 g of coated granule (u), 29.3 g ofethylcellulose, 3 g of light anhydrous silicic acid, 1.5 g of magnesiumstearate, and 1.5 g of talc. The mixture was uniformly blended and thencompressed and molded. The resulting tablets each weighed 300 mg and hada diameter of 9 mm. These tablets were taken as compressed-moldedpreparation (v) of the present invention.

Example 11

1) Preparation of Non-coated Granule (w):

525 g of diclofenac sodium, 55 g of talc, and 140 g of corn starch weremixed and pulverized, resulting in fine powders. These fine powders wereprocessed to produce spherical granules, using 480 g of purified sucrosethat had been obtained by shifting through 24-28 mesh as a core, whilepouring a liquid consisting of 27 g of hydroxypropyl cellulose dissolvedin 513 g of ethyl alcohol. The granules were dried for 3 hours at 55° C.Non-coated granules (w) were taken as the dried granules which passedthrough 14 mesh but not 32 mesh.

2) Preparation of Coated Granule (x):

Coated granules (x) were produced according to a conventional spraycoating method as follows: 600 g of non-coated granule (w) was placedinto a fluid-type coating apparatus followed by spray coating using 2083g of the coating liquid having a composition shown below. The weight ofthe coating with respect to the weight of the non-coated granule was25%.

    ______________________________________                                        Composition of the Coating Liquid                                                                     %                                                     ______________________________________                                        Aminoalkyl methacrylate copolymer-S                                                                   6.5                                                   Glycerin ester of fatty acid                                                                          0.5                                                   Talc                    0.2                                                   Ethyl alcohol           92.8                                                  Total                   100.0                                                 ______________________________________                                    

3) Preparation of Compressed-Molded Preparation (y):

240 g of an aqueous solution of hydroxypropyl cellulose were added to apowder mixture consisting of 45 g of diclofenac sodium, 500 g ofethylcellulose, 119 g of lactose, 40 g of corn starch and 24 g ofcroscarmellose sodium Type A. The mixture was then kneaded and granuleswere produced according to a conventional method. Next, 376 g of thegranules obtained, 153.4 g of coated granules (x), 58.6 g of ethylcellulose, 6 g of light anhydrous silicic acid, 3 g of magnesiumstearate, and 3 g of talc were uniformly mixed and then compressed andmolded to produce tablets. The weight of each tablet was 300 mg and thediameter was 9 mm. These tablets were taken as compressed-moldedpreparation (y) of the present invention.

Test Example 6

The dissolution of active ingredient from compressed-molded preparations(v) obtained from Example 10 and (y) obtained from Example 11, as wellas their respective fine powders for use for tablets, were measured bythe rotating paddle method (Japan Pharmacopeia, 11th Edition). A pH of4.5 buffer test solution was used from the beginning of the test until30 min, while after that a pH of 7.5 buffer test solution was used. Theresults are shown in Table 7. No changes in the dissolutions of activeingredient were observed for the compressed-molded preparations of thepresent invention between before and after compression-molding. Also,active ingredient of the compressed-molded preparation (v), whichcontained organic acids, was more slowly released than that ofcompressed-molded preparation (y) which did not contain organic acids.

                  TABLE 7                                                         ______________________________________                                        Time    Dissolution (%)                                                       (min)   (v)    (v) fine powders                                                                            (y)  (y) fine powders                            ______________________________________                                        30 (pH 4.5)                                                                           29.5   30.8          32.3 30.2                                        60 (pH 7.5)                                                                           68.4   67.7          98.2 98.6                                        90 (pH 7.5)                                                                           95.6   94.8          99.5 99.4                                        ______________________________________                                    

Example 12

1) Preparation of Double-layered Granules (z):

Double-layer coated granules (z) were produced according to aconventional spray coating method as follows; 600 g of the coatedgranules (u) from 2) of Example 10 were placed into a fluid-type coatingapparatus followed by spray coating using 1667 g of the coating liquidhaving a composition shown below. The weight of the coating with respectto the weight of coated granules (u) was 20%.

    ______________________________________                                        Composition of Coating Liquid                                                                       %                                                       ______________________________________                                        Hydroxypropyl methylcellulose                                                                       6.5                                                     Macrogol 6000         0.5                                                     Talc                  0.2                                                     Ethyl alcohol         66.8                                                    Purified water        26.0                                                    Total                 100.0                                                   ______________________________________                                    

2) Preparation of Compressed-Molded Preparation (A):

240 g of an aqueous solution of hydroxypropyl cellulose (10% w/w) wereadded to a powder mixture consisting of 45 g of diclofenac sodium, 500 gof ethylcellulose, 119 g of lactose, 40 g of corn starch, and 24 g ofA-type croscarmellose sodium Type A. The mixture was kneaded and thengranules were produced according to a conventional method. Next, 376 gof the granules obtained was mixed with 184.1 g of double-layer coatedgranules (z), 27.9 g of microcrystalline cellulose, 6 g of lightanhydrous silicic acid, 3 g of magnesium stearate and 3 g of talc. Afteruniformly blending the mixture, compression and molding were carriedout. The weight of the tablets was 300 mg and the diameter 9 mm. Thesetablets were taken as compressed-molded preparation (A) of the presentinvention.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

What is claimed as new and desired to be secured by Letters Patentis:
 1. A compressed-molded preparation consisting essentially of:a)coated granules of a pharmaceutical composition comprising apharmaceutically active component in the core; b) a non-coated componentconsisting essentially of 10% or more by weight of a non-swellingpolymer selected from the group consisting of ethyl cellulose, aminoalkyl methacrylate copolymer, polyvinyl acetate, polyvinyl chloride,polyethylene, cellulose acetate phthalate, hydroxypropyl methylcellulosephthalate, hydroxypropyl methylcellulose acetate succinate,carboxymethyl ethylcellulose, styrene-acrylic acid copolymer,methacrylic acid copolymer, maleic anhydride copolymer, polyvinylacetaldiethylamine acetate, aminoalkyl methacrylate copolymer E, hydroxypropylmethylcellulose, methylcellulose, hydroxypropyl cellulose,polyvinylpyrrolidone, and mixtures thereof; wherein said coated granulesare compressed and molded together with said non-coated component. 2.The compressed-molded preparation of claim 1, wherein the coating ofsaid coated granules is one member selected from the group consisting ofwater insoluble polymers, intestinally soluble polymers, paraffin waxes,higher alcohols, higher fatty acid esters, higher fatty acids, salts ofhigher fatty acids, acid soluble polymers, water soluble polymers, andmixtures thereof.
 3. The compressed-molded preparation of claim 1,wherein said core of said coated granules comprises diclofenac sodium assaid pharmaceutically active component and a pharmaceutically acceptableorganic acid, and the coating of said coated granules is asustained-release coating.
 4. The compressed-molded preparation of claim3, wherein said sustained-release coating comprises one member selectedform the group consisting of water insoluble polymers, intestinallysoluble polymers, paraffin waxes, higher alcohols, higher fatty acidesters, higher fatty acids, salts of higher fatty acids and mixturesthereof.
 5. The compressed-molded preparation according to claim 1,wherein said non-coated component consists essentially of non-swellingpolymers and the pharmaceutically active component.